Geometric Control of YAP-dependent Mechanotransduction: A Proposed Model

The Billiar lab is interested in the interplay between mechanical tension and programmed cell death (namely, apoptosis) in cells growing on micro-contact printed aggregates. The Billiar lab uses a bioinspired hydrogel to develop an in vitro model for mechanosensitive signaling in mammalian cells. The micro-contact printed cell aggregates experience a loss of tensional homeostasis at the center of the aggregates, which results in selective cell death at the center, but not periphery of the aggregates, followed by calcification, similar to excised diseased aortic valves. However, the subcellular mechanisms responsible for transducing the mechanical cues from the loss of tensional homeostasis to pro-apoptotic signaling have yet to be elucidated; the Billiar lab is interested in finding this link. Mechanotransduction is the functional link between mechanical cues and the consequent subcellular biochemical response.1 Cells sense and respond to their physical surroundings via cell-cell junctions, cell-matrix adhesions, and intracellular actin networks.1 For example, in epithelial cells, restriction of cell growth to spatially patterned circular arrays leads to (1) increased proliferation and (2) higher tractional stresses at the periphery than at the center.2-3 Proliferation at the periphery of these circular cell aggregates is YAP-dependent, with nuclear localization of YAP at the periphery.4 Transcriptional co-activator YAP is (1) a nuclear relay of mechanical signals,5 (2) the main transcriptional effector of the Hippo pathway,6 and (3) involved in both proliferation (via TEAD promoter) and apoptosis (via p73 promoter).7 Cell competition is an apoptosis-dependent cell communication phenomenon based on cell fitness comparisons, and which creates “loser” cells that die via apoptosis and “winner” cells that survive.8-9 For example, co-culture of TEAD-activity-manipulated fibroblasts with WT induces cell competition, in which cells with higher TEAD activity “won,” and cells with lower TEAD activity “lost” (underwent apoptosis).10 Hypothesis: Culture of fibroblasts in geometrically constrained, circular cell aggregates induces cell competition via the formation of “winner” and “loser” cell populations due to differences in tensional homeostasis experienced at the periphery vs. center of the aggregates

Directed Cellular Self-Assembly to Fabricate Cell-Derived Tissue Rings for Biomechanical Analysis and Tissue Engineering

Each year, hundreds of thousands of patients undergo coronary artery bypass surgery in the United States.1 Approximately one third of these patients do not have suitable autologous donor vessels due to disease progression or previous harvest. The aim of vascular tissue engineering is to develop a suitable alternative source for these bypass grafts. In addition, engineered vascular tissue may prove valuable as living vascular models to study cardiovascular diseases. Several promising approaches to engineering blood vessels have been explored, with many recent studies focusing on development and analysis of cell-based methods.2-5 Herein, we present a method to rapidly self-assemble cells into 3D tissue rings that can be used in vitro to model vascular tissues

Biomechanical investigation of a novel ratcheting arthrodesis nail

<p>Abstract</p> <p>Background</p> <p>Knee or tibiotalocalcaneal arthrodesis is a salvage procedure, often with unacceptable rates of nonunion. Basic science of fracture healing suggests that compression across a fusion site may decrease nonunion. A novel ratcheting arthrodesis nail designed to improve dynamic compression is mechanically tested in comparison to existing nails.</p> <p>Methods</p> <p>A novel ratcheting nail was designed and mechanically tested in comparison to a solid nail and a threaded nail using sawbones models (Pacific Research Laboratories, Inc.). Intramedullary nails (IM) were implanted with a load cell (Futek LTH 500) between fusion surfaces. Constructs were then placed into a servo-hydraulic test frame (Model 858 Mini-bionix, MTS Systems) for application of 3 mm and 6 mm dynamic axial displacement (n = 3/group). Load to failure was also measured.</p> <p>Results</p> <p>Mean percent of initial load after 3-mm and 6-mm displacement was 190.4% and 186.0% for the solid nail, 80.7% and 63.0% for the threaded nail, and 286.4% and 829.0% for the ratcheting nail, respectively. Stress-shielding (as percentage of maximum load per test) after 3-mm and 6-mm displacement averaged 34.8% and 28.7% (solid nail), 40.3% and 40.9% (threaded nail), and 18.5% and 11.5% (ratcheting nail), respectively. In the 6-mm trials, statistically significant increase in initial load and decrease in stress-shielding for the ratcheting vs. solid nail (<it>p </it>= 0.029, <it>p </it>= 0.001) and vs. threaded nail (<it>p </it>= 0.012, <it>p </it>= 0.002) was observed. Load to failure for the ratcheting nail; 599.0 lbs, threaded nail; 508.8 lbs, and solid nail; 688.1 lbs.</p> <p>Conclusion</p> <p>With significantly increase of compressive load while decreasing stress-shielding at 6-mm of dynamic displacement, the ratcheting mechanism in IM nails may clinically improve rates of fusion.</p

Displacement Across a Fracture Gap with Axial Loading of Far Cortical Locking Constructs

Purpose: Far cortical locking has been proposed for reducing stiffness and promoting greater dynamic stability in locked plating constructs. Prior studies have shown reduced stiffness with axial loading of these constructs, leading to a theoretical increase in inter-fragmentary motion and secondary bone healing. The purpose of this study was to examine strain across a fracture gap using far cortical locking constructs in a biomechanical model of distal femoral fractures. Methods: Fourth generation sawbones were cut transversely along the distal diaphysis and plated with distal femoral buttress plates and cortical locking screws. Far cortical locking (FCL) specimens were predrilled in the lateral cortex and control specimens were plated with a standard locked plating construct. The constructs were loaded sequentially with 100, 200, and 400 lbs of force on a mechanical test frame. Displacement across the fracture gap measured in pixels using an optical system. Results: Strain across the fracture gap increased with progressive loading from zero to 400 lbs in both groups. Strain also decreased in a linear fashion from medial to lateral across the fracture gap in both constructs (Figure 1). Standard locking constructs exhibited an average 28% greater strain than the far cortical locking constructs at all loading forces. Control specimens exhibited greater lateral displacement of the distal segment relative to the plate (Figure 2), consistent with higher shear forces compared to FCL specimens. Conclusions: In all specimens, there was considerable strain seen with loading that increased in characteristic fashion from lateral to medial. Overall, FCL constructs exhibited both lower strain, and importantly, lower shear, than measured in controls. This biomechanical model suggests that FCL changes loading across the femoral diaphysis in complex ways, and that assumptions about strain approaching zero on the lateral side of the distal femur with conventional locking or FCL may be incorrect

Morphological and stress vulnerability indices for human coronary plaques and their correlations with cap thickness and lipid percent: An IVUS-based fluid-structure interaction multi-patient study

Plaque vulnerability, defined as the likelihood that a plaque would rupture, is difficult to quantify due to lack of in vivo plaque rupture data. Morphological and stress-based plaque vulnerability indices were introduced as alternatives to obtain quantitative vulnerability assessment. Correlations between these indices and key plaque features were investigated. In vivo intravascular ultrasound (IVUS) data were acquired from 14 patients and IVUS-based 3D fluid-structure interaction (FSI) coronary plaque models with cyclic bending were constructed to obtain plaque wall stress/strain and flow shear stress for analysis. For the 617 slices from the 14 patients, lipid percentage, min cap thickness, critical plaque wall stress (CPWS), strain (CPWSn) and flow shear stress (CFSS) were recorded, and cap index, lipid index and morphological index were assigned to each slice using methods consistent with American Heart Association (AHA) plaque classification schemes. A stress index was introduced based on CPWS. Linear Mixed-Effects (LME) models were used to analyze the correlations between the mechanical and morphological indices and key morphological factors associated with plaque rupture. Our results indicated that for all 617 slices, CPWS correlated with min cap thickness, cap index, morphological index with r = -0.6414, 0.7852, and 0.7411 respectively (p<0.0001). The correlation between CPWS and lipid percentage, lipid index were weaker (r = 0.2445, r = 0.2338, p<0.0001). Stress index correlated with cap index, lipid index, morphological index positively with r = 0.8185, 0.3067, and 0.7715, respectively, all with p<0.0001. For all 617 slices, the stress index has 66.77% agreement with morphological index. Morphological and stress indices may serve as quantitative plaque vulnerability assessment supported by their strong correlations with morphological features associated with plaque rupture. Differences between the two indices may lead to better plaque assessment schemes when both indices were jointly used with further validations from clinical studies

Quantification of patient-specific coronary material properties and their correlations with plaque morphological characteristics: An in vivo IVUS study

BACKGROUND: A method using in vivo Cine IVUS and VH-IVUS data has been proposed to quantify material properties of coronary plaques. However, correlations between plaque morphological characteristics and mechanical properties have not been studied in vivo. METHOD: In vivo Cine IVUS and VH-IVUS data were acquired at 32 plaque cross-sections from 19 patients. Six morphological factors were extracted for each plaque. These samples were categorized into healthy vessel, fibrous plaque, lipid-rich plaque and calcified plaque for comparisons. Three-dimensional thin-slice models were constructed using VH-IVUS data to quantify in vivo plaque material properties following a finite element updating approach by matching Cine IVUS data. Effective Young\u27s moduli were calculated to represent plaque stiffness for easy comparison. Spearman\u27s rank correlation analysis was performed to identify correlations between plaque stiffness and morphological factor. Kruskal-Wallis test with Bonferroni correction was used to determine whether significant differences in plaque stiffness exist among four plaque groups. RESULT: Our results show that lumen circumference change has a significantly negative correlation with plaque stiffness (r = -0.7807, p = 0.0001). Plaque burden and calcification percent also had significant positive correlations with plaque stiffness (r = 0.5105, p \u3c 0.0272 and r = 0.5312, p \u3c 0.0193) respectively. Among the four categorized groups, calcified plaques had highest stiffness while healthy segments had the lowest. CONCLUSION: There is a close link between plaque morphological characteristics and mechanical properties in vivo. Plaque stiffness tends to be higher as coronary atherosclerosis advances, indicating the potential to assess plaque mechanical properties in vivo based on plaque compositions

Microsoft Word - SBC2008 Billiar - boundary stiffness regulation 3.doc

ABSTRACT Recent studies utilizing compliant culture substrates clearly demonstrate that many cell behaviors such as migration and contraction are strongly influenced by the stiffness of the local environment. The goal of this work was to develop a method for studying stiffness-dependent biology within 3D cell-populated gels without altering the biochemical environment of the gel. A device was developed utilizing compliant anchors to tune the boundary stiffness of suspended collagen gels. Human fibroblasts compacted the gels to a greater extent as the stiffness of the anchors was decreased. Further, the force generated by the cells increased with increased boundary stiffness, and the response of the cells to TGF-β1 was accentuated as the stiffness increased. This new method represents a promising tool for the controlled study of stiffness-dependent biology within tissuelike 3D environments

Problem-Based Learning in Biomechanics: Advantages, Challenges, and Implementation Strategies

Problem-based learning (PBL) has been shown to be effective in biomedical engineering education, particularly in motivating student learning, increasing knowledge retention, and developing problem solving, communication, and teamwork skills. However, PBL adoption remains limited by real challenges in effective implementation. In this paper, we review the literature on advantages and challenges of PBL and present our own experiences. We also provide practical guidelines for implementing PBL, including two examples of PBL modules from biomechanics courses at two different institutions. Overall, we conclude that the benefits for both professors and students support the use of PBL in biomedical engineering education